During the past year, our research included: (1) studies of genetic and environmental mechanisms that produce low cerebrospinal fluid concentrations of 5-hydroxyindoleacetic acid (CSF 5-HIAA) concentrations and alcohol consumption. Using pedigree analyses we were able to show for the first time that alcohol consumption is heritable in nonhuman primates, with fathers' and mothers' contributions accounting for about 30% of the variance in alcohol consumption. Early deleterious rearing environments and being solitary while drinking also increased the consumption of alcohol. In collaboration with Drs. K. Peter Lesch and Armin Heils at the University of Wuerzberg, Germany, we found evidence of an environment-dependent association between length variation in a variant of the 5-HT transporter gene region (5-HTTLPR, rh5-HTTLPR in rhesus) and CSF 5-HIAA concentrations in rhesus monkeys. Strain differences in both allele frequency and CSF 5-HIAA levels were also identified. Rhesus monkeys given the early deleterious experience of parental deprivation and then reared in absence of adults were differentiated by genotype in CSF 5-HIAA concentrations, whereas mother-reared monkeys were not differentiated. (2) the development of new technologies to study individual chronic alcohol consumption. This computerized methodology enabled us to identify individual monkeys living in large social groups, dispense alcohol to them, measure individual consumption patterns, thus allowing us to characterize large numbers of monkeys as high and low alcohol consumers. This methodology will allow us for the first time to study chronic alcohol consumption for 24-hours a day and enable other researchers interested in modeling alcohol consumption in primates to perform such studies using limited personnel resources. (3) pharmacological treatment studies of aggression, self-injurious behavior, and alcohol consumption. These studies showed that administration of tryptophan increased CNS serotonin functioning and eliminated self-injurious behavior. Treatments with the serotonin reuptake inhibitor sertraline reduced aggression and alcohol consumption in aggressive adult males. (4) studies investigating the role that the HPA system plays in alcohol consumption and its related behaviors. In one study we showed that high levels of plasma cortisol in infancy, obtained during a stressful experience, were predictive of high alcohol consumption three years later, when subjects were adolescents. Oral administration of a corticotrophin releasing hormone (CRH) antagonist reduced CSF CRH concentrations and plasma cortisol concentrations of as well as reducing their arousal. Studies in the next year will investigate its potential as a treatment for excessive alcohol consumption. (5) investigations of the role that taste plays in excessive consumption and whether an affinity for reinforcing agents such as sugar solutions are positively correlated with high alcohol consumption. In collaboration with Dr. Jim Woods at the University of Michigan studies showed that in high alcohol consuming monkeys, alcohol consumption remained high even when the alcohol solution was unsweetened, indicating that gustatory factors are not primary in producing high alcohol consumption; (6) comparisons of alcohol consumption between NIH rhesus monkeys and rhesus monkeys purchased at random: In this collaboration with Dr. Woods, we were able to show that NIH high alcohol consuming monkeys consume more alcohol than the typical monkeys picked at random, and that high alcohol consumption at the NIH in Poolesville predicts high consumption one year later in Michigan, using different methodologies. Furthermore, this preference for alcohol in NIH monkeys was evident over a wide variety of concentrations. The NIH high alcohol consuming monkeys also exhibited low CSF 5-HIAA concentrations, and independent of stock type, high consuming monkeys were more likely to exhibit low CSF 5-HIAA concentrations. Interestingly, high alcohol consumption was not correlated with high use of opiates or other reinforcing agents, indicating that preference for alcohol is not a generalized drug preference pattern and instead this preference is unique to alcohol. (7) a new program of study to investigate cognitive functioning and impulsivity in monkeys prone to high alcohol consumption and/or low CSF 5-HIAA concentrations. New methodologies were initiated to test monkey cognitive skills using a joystick and a computer. This methodology allows experimenters to vary experimental demands to test specific parameters of cognition in a primate. Low CSF 5-HIAA concentrations were associated with high impulsivity, as measured by approach and extension of limbs into of a novel opaque, black chamber with salient reinforcers located inside. Early deleterious rearing experiences produced subjects who were slow to attempt novel cognitive tasks. Dopamine and norepinephrine metabolite levels were associated with greater response to reward and higher arousal, respectively. (8) a collaboration was initiated with Drs. Salem and Hibbeln (LMBB) to investigate the role of essential fatty acids in CNS serotonin functioning. Infants fed a diet high in essential fatty acids were shown to be advanced in development and exhibited less fear-related behavior. As a corollary of this investigation, a laboratory-wide assessment of cholesterol and essential fatty acids were made in about 100 subjects to correlate with CSF 5-HIAA concentrations and violent behavior. Initial findings indicate that high CNS testosterone and low glucose were correlated with high rates of aggression in adolescent monkeys. Assays are underway to complete these analyses.
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